A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress |
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| Authors: | Yunhao Liu Caitlin Collins William B. Kiosses Ann M. Murray Monika Joshi Tyson R. Shepherd Ernesto J. Fuentes Ellie Tzima |
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| Affiliation: | 1.Department of Cell Biology and Physiology, McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;2.Core Microscopy Facility, The Scripps Research Institute, La Jolla, CA 92037;3.Department of Biochemistry, and 4.Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242 |
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| Abstract: | Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE-cadherin–p67phox–Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase. |
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